Cardiolipin: a missing link between a-synuclein and mitochondria dysfunction

Original article: Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein, Nature Communications: February 26, 2018. 

The takeaway

One of the open questions in understanding neuronal damage in Parkinson’s is how dysfunction in mitochondria, the powerhouses of the cell, and alpha-synuclein, a protein whose abnormal form is associated with Parkinson’s, might be linked. This series of experiments identifies cardiolipin, a type of lipid, as a potential missing link. Cardiolipin refolds alpha-synuclein and in this process mitochondrial degradation is prevented, but it cannot refold abnormal alpha-synuclein. As a result, mitochondria become damaged and degraded, causing significant damage to neurons. Anti-alpha-synuclein antibodies can stop the cell to cell spread of abnormal alpha-synuclein and prevent mitochondrial dysfunction.

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Why is it important?

The identification of cardiolipin as one of the links between mitochondrial dysfunction and alpha-synuclein sheds light onto important mechanisms that are known to affect the survival of neurons in Parkinson’s. Stopping the spread of alpha-synuclein to healthy neurons could be key in preventing mitochondrial dysfunction.

Background

Mitochondria are the powerhouses of the cell, and represent the main site of energy production. There is a lot of evidence that mitochondrial dysfunction, and eventually the destruction of mitochondria within the cell (a process known as mitophagy), contributes to the loss of nerve cells in Parkinson’s.

In addition, alpha-synuclein is a protein also found in neurons, and is believed to have a number of functions that help them communicate with each other. In Parkinson’s, abnormal a-synuclein takes on a different shape which causes it to fold abnormally into clumps that damage neurons. But could there be a link between these two processes? Does abnormal a-synuclein directly damage mitochondria and if so how?

The details

A series of experiments tackled this important question head on. In neurons with alpha-synuclein genetic mutations, mitochondria were fragmented and smaller. Abnormal alpha-synuclein could be found on the outer surface of mitochondria even before fragmentation began, indicating this was the likely cause.

Cardiolipin is a lipid found in mitochondria, and moves to their surface, or outer membrane, under conditions of cellular stress to help its appropriate degradation. Both abnormal alpha-synulein and exposure to a toxic pesticide caused cardiolipin to move in this way, before mitochondrial degradation occurred.

By mixing cardiolipin with synthetic alpha-synuclein, these authors showed that cardiolipin’s role is to refold misfolded alpha-synuclein and prevent mitochondrial degradation. Abnormal alpha-synuclein can’t be refolded so mitochondria undergo destruction.

Finally, these researchers were also able to show that abnormal alpha-synuclein can spread to healthy neurons, and that this spread could be blocked by an antibody.

Next steps

Future studies must assess the long term efficacy of vaccination against alpha-synuclein in larger cohorts of patients.

Original article: Ryan T, Bamm VV, Stykel MG, Coackley CL, Humphries KM, Jamieson-Williams R, Ambasudhan R, Mosser DD, Lipton SA, Harauz G, Ryan SD. February 26, 2018. Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein: Nature Communications

 

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